A variety of tissues metabolize estrogen (as a representative phenolic A-ring steroid) to various degrees. Of all of the tissues investigated, cornea appears to be the most active estrogen-metabolizing tissue (Stàrka, L and J Obenberger, “In vitro Estrone-Estradiol-17β Interconversion in the Cornea, Lens, Iris and Retina of the Rabbit Eye,” Arch Klin Exp Ophthalmol, 196:199–204 (1975)). Estrogens have demonstrated an important role in the health maintenance of all mucous membranes in the body, including the maintenance of a healthy ocular surface. Additional studies have revealed that the biological activity of estrogen may be effective in the protection and treatment of the eye, including the lens and retina, against cataracts and the detrimental effects of glaucoma.
Unfortunately, many regions of the eye are relatively inaccessible to systemically administered estrogens. For example, orally administered estrogen passes through the liver before reaching estrogen sensitive tissues. Because the liver contains enzymes that can inactivate the estrogen, the estrogen that eventually reaches tissue targeted for treatment is virtually ineffective. Moreover, systemic administration of estrogen often produces undesirable side effects, i.e., feminizing side effects in men.
As a result, topical drug delivery remains the preferred route of administration to the eye. There are a variety of factors that affect the absorption of drugs into the eye. These factors include: the instillation volume of the drug, the frequency of instilled drug administration, the structure and integrity of the cornea, the protein level in tears, the level of enzymes in tears, lacrimal drainage and tear turnover rate, as well the rate of adsorption and absorption of a drug by the conjunctiva, sclera, and eyelids.
Thus, the potential treatment of ocular disorders/conditions by estrogens or agents derived from estrogens is confounded by poor ocular bioavailability of pharmacologically active agents and by the likelihood of triggering systemic side effects associated with the administration of natural (endogenous) estrogens. The latter are due to absorption from the nasal cavity and the gastrointestinal (GI) tract after the topically administered estrogen hormone gains access to these pathways through its removal by the nasolacrimal apparatus of the eye. A potential way of reducing or even eliminating systemic side effects is to improve ocular targeting that would allow for the use of reduced doses of the biologically active agent in the ophthalmic drug formation.
Accordingly, the direct administration to an eye lens of estrogen having quinolines (i.e., 6-hydroxyquinoline) and fused quinolines that act as steroid receptor modulators to prevent or treat cataract disorders has been disclosed. In addition, the administration of 17-β-estradiol to the surface of the eye to alleviate dry-eye syndrome or keratoconjunctivitis sicca has been disclosed. Glycosides of catechol estrogens have been formulated that demonstrate antioxidant activity to the same degree as to that of the parent catechol estrogens. Nonetheless, all of the previously disclosed compounds and methods for applying estrogens to the eye relate to compounds that lack efficient corneal penetration and/or are unapplicable to men because of their activity as a female hormone.
As noted above, the major barrier to ocular drug penetration is the cornea. The cornea is composed of three layers: a lipid-rich epithelium, a lipid-poor soma, and a lipid-rich endothelium. Therefore, an agent must possess both lipophilic-hydrophilic balance for adequate transcorneal penetration and, thus, ocular bioavailability (Akers H J, “Ocular bioavailability of topically applied ophthalmic drugs,” Am Pharm, NS23:33–36 (1983)). Thus, poor ocular bioavailability is an issue for estrogens and their synthetic analogs, because estrogens are highly lipid soluble molecules that are usually not amenable to adequate transcorneal penetration.
Prodrugs are inactive compounds that are converted in vivo into biologically active agents by enzymatic and/or chemical transformations. Prodrugs are advantageous because they can be designed to overcome problems associated with stability, toxicity, lack of specificity, or limited bioavailability, that may exist with the active form of a drug. Thus, there is a need to develop effective prodrugs of estrogen as a medical compound.
Estrogen quinols have been known for decades among organic chemists (Gold A. M., and Schwenk E., “Synthesis and reaction of steroidal quinols,” J Am Chem Soc, 80:5683–5687 (1958)) though their metabolic formation has only been reported recently (Ohe T., et al., “Novel metabolic pathway of estrone and 17β-estradiol catalyzed by cytochrome P-450”, Drug Metab Dispos, 28:11–112 (2000)). 10β-hydroxy-1,4-estradiene-3,7-dione and 10β,17β-dihydroxy-1,4-estradiene-3-one were detected from the respective estrogens during metabolic oxidation catalyzed by several cytochrome P-450 isoenzymes in rat liver microsomal systems. Contrary to well-known catechol metabolites of estrogens (Zhu, B. T. and Conney A. H., “Functional role of estrogen metabolism in target cells: review and perspective,” Carcinogenesis, 19:1–27 (1998)), quinols do not possess an aromatic A-ring, making their biochemistry substantially different from that of catechols. Studies are currently underway to assess the nature of estrogen quinols.